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Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer

Journal of Cancer Research and Clinical Oncology volume 136, pages 571–576 (2010)Cite this article

Abstract

Background

Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti-tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer.

Methods

GDF-15 null (Gdf15 −/−) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc min/+ were bred. Gdf15 −/−, Apc min/+ and Gdf15 +/+, Apc min/+ mice were generated.

Results

In Gdf15 −/−, Apc min/+ mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15 +/+, Apc min/+ mice. Sulindac chemoprotection activity although potent in Gdf15 +/+, Apc min/+ mice was abolished in Gdf15 −/−, Apc min/+ mice.

Conclusions

These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer.

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References

  • Antonakopoulos N, Karamanolis DG (2007) The role of NSAIDs in colon cancer prevention. Hepatogastroenterology 54:1694–1700

    CAS  PubMed  Google Scholar 

  • Babbar N, Ignatenko NA, Casero RA Jr, Gerner EW (2003) Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J Biol Chem 278:47762–47775

    Article  CAS  PubMed  Google Scholar 

  • Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE (2001) Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59:901–908

    CAS  PubMed  Google Scholar 

  • Baek SJ, Okazaki R, Lee SH, Martinez J, Kim JS, Yamaguchi K, Mishina Y, Martin DW, Shoieb A, McEntee MF, Eling TE (2006) Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia. Gastroenterology 131:1553–1560

    Article  CAS  PubMed  Google Scholar 

  • Barnes CJ, Lee M (1998) Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114:873–877

    Article  CAS  PubMed  Google Scholar 

  • Beazer-Barclay Y, Levy DB, Moser AR, Dove WF, Hamilton SR, Vogelstein B, Kinzler KW (1996) Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis 17:1757–1760

    Article  CAS  PubMed  Google Scholar 

  • Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo XJ, Ramonetti JT, Abreu-Goris M, Newmark HL, Lipkin ML, DeCosse JJ, Bertagnolli MM (1996) Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 56:2556–2560

    CAS  PubMed  Google Scholar 

  • Bottone FG Jr, Martinez JM, Alston-Mills B, Eling TE (2004) Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells. Carcinogenesis 25:349–357

    Article  CAS  PubMed  Google Scholar 

  • Brown DA, Ward RL, Buckhaults P, Liu T, Romans KE, Hawkins NJ, Bauskin AR, Kinzler KW, Vogelstein B, Breit SN (2003) MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma. Clin Cancer Res 9:2642–2650

    CAS  PubMed  Google Scholar 

  • Buckhaults P, Rago C, St Croix B, Romans KE, Saha S, Zhang L, Vogelstein B, Kinzler KW (2001) Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res 61:6996–7001

    CAS  PubMed  Google Scholar 

  • Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L, AB PL (1997) a novel placental bone morphogenetic protein. Biochim Biophys Acta 1354:40–44

    CAS  PubMed  Google Scholar 

  • Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ (2000a) Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 20:3742–3751

    Article  CAS  PubMed  Google Scholar 

  • Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ (2000b) Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol Cell Biol 2:3742–3751

    Article  Google Scholar 

  • Jang TJ, Kang HJ, Kim JR, Yang CH (2004) Non-steroidal anti-inflammatory drug activated gene (NAG-1) expression is closely related to death receptor-4 and -5 induction, which may explain sulindac sulfide induced gastric cancer cell apoptosis. Carcinogenesis 25:1853–1858

    Article  CAS  PubMed  Google Scholar 

  • Kim KS, Baek SJ, Flake GP, Loftin CD, Calvo BF, Eling TE (2002) Expression and regulation of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in human and mouse tissue. Gastroenterology 122:1388–1398

    Article  CAS  PubMed  Google Scholar 

  • Kim KS, Yoon JH, Kim JK, Baek SJ, Eling TE, Lee WJ, Ryu JH, Lee JG, Lee JH, Yoo JB (2004) Cyclooxygenase inhibitors induce apoptosis in oral cavity cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene. Biochem Biophys Res Commun 325:1298–1303

    Article  CAS  PubMed  Google Scholar 

  • Kim JS, Baek SJ, Sali T, Eling TE (2005) The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15. Mol Cancer Ther 4:487–493

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Chang JH, Rhee KH, Yoon JH, Kwon SH, Song K, Lee KW, Cho CI, Jeon JH, Kim KS (2008) Cyclooxygenase inhibitors induce apoptosis in sinonasal cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene. Int J Cancer 122:1765–1773

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hamilton SR, Hedge P, Markham A et al (1991) Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251:1366–1370

    Article  CAS  PubMed  Google Scholar 

  • Koniaris LG (2003) Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J Gastrointest Surg 7:901–905

    Article  PubMed  Google Scholar 

  • Pang RP, Zhou JG, Zeng ZR, Li XY, Chen W, Chen MH, Hu PJ (2007) Celecoxib induces apoptosis in COX-2 deficient human gastric cancer cells through Akt/GSK3beta/NAG-1 pathway. Cancer Lett 251:268–277

    Article  CAS  PubMed  Google Scholar 

  • Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD (1998) Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem 273:13760–13767

    Article  CAS  PubMed  Google Scholar 

  • Park JY, Park KH, Bang S, Kim MH, Koh SS, Song SY (2008) Expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inversely correlates with tumor progression in gastric adenomas and carcinomas. J Cancer Res Clin Oncol 134(9):1029–1035

    Article  CAS  PubMed  Google Scholar 

  • Rigas B, Kashfi K (2005) Cancer prevention: a new era beyond cyclooxygenase-2. J Pharmacol Exp Ther 314:1–8

    Article  CAS  PubMed  Google Scholar 

  • Sarkar FH, Adsule S, Li Y, Padhye S (2007) Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem 7:599–608

    Article  CAS  PubMed  Google Scholar 

  • Yamada Y, Mori H (2007) Multistep carcinogenesis of the colon in Apc(Min/+) mouse. Cancer Sci 98:6–10

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama-Kobayashi M, Saeki M, Sekine S, Kato S (1997) Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J Biochem (Tokyo) 122:622–626

    CAS  Google Scholar 

  • Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG (2005) Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 23:543–548

    CAS  PubMed  Google Scholar 

  • Zimmers TA, Jin X, Hsiao EC, Perez EA, Pierce RH, Chavin KD, Koniaris LG (2006) Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms. J Surg Res 130:45–51

    Article  CAS  PubMed  Google Scholar 

  • Zimmers TA, Gutierrez JC, Koniaris LG (2007) NAG-1/GDF-15: no evidence for an inhibitory role in colon cancer? Gastroenterology 132:1204–1205 author reply 1205

    Article  PubMed  Google Scholar 

  • Zimmers TA, Jin X, Gutierrez JC, Acosta C, McKillop IH, Pierce RH, Koniaris LG (2008) Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis. J Cancer Res Clin Oncol 134(7):753–759

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Alexis Sloan for help with the mice. Financial support was received from Sylvester Comprehensive Cancer Center, Dewitt Daughtry Family Department of Surgery, and the Papanicolaou Corps for Cancer Research (TAZ and LGK).

Conflict of interest statement

None of the authors has any personal or financial conflicts to declare.

Author information

Affiliations

  1. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Teresa A. Zimmers, Juan C. Gutierrez & Leonidas G. Koniaris

  2. Department of Cell Biology and Anatomy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 3550 SCCC (310T), 1475 NW 12th Ave, Miami, 33136, FL, USA

    Teresa A. Zimmers & Leonidas G. Koniaris

Authors
  1. Teresa A. Zimmers
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  2. Juan C. Gutierrez
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  3. Leonidas G. Koniaris
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Corresponding author

Correspondence to Teresa A. Zimmers.

Additional information

T. A. Zimmers and J. C. Gutierrez contributed equally to this report.

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Zimmers, T.A., Gutierrez, J.C. & Koniaris, L.G. Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer. J Cancer Res Clin Oncol 136, 571–576 (2010). https://doi.org/10.1007/s00432-009-0691-4

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  • DOI: https://doi.org/10.1007/s00432-009-0691-4

Keywords

  • NSAID
  • Colon cancer
  • COX-2
  • Cytokine
  • TGF-beta